PROJECT SUMMARY/ABSTRACT This K01 award will provide the training and mentored research experience needed for me to become an independent researcher with a focus on improving the health outcomes of patients with or at risk for chronic viral infections. Chronic hepatitis C virus (HCV) infection affects over 3 million people in the U.S., with 80,000 HCV-related deaths per year. The health impacts of HCV are more severe in human immunodeficiency virus (HIV) patients, in whom HCV-associated liver disease is the leading cause of non-AIDS-related death. HIV/HCV coinfection has also been linked to an increased risk of extrahepatic outcomes, including cardiovascular and kidney disease. With the emergence of interferon-free regimens, most HCV patients can now be cured, regardless of HIV status. However, critical questions remain about 1) the effect of the timing of HCV treatment on hepatic and extrahepatic outcomes, 2) the ongoing risk of hepatic and extrahepatic outcomes after HCV cure, and 3) whether the clinical benefits of HCV treatment in early stages of liver disease warrant the use of costly new regimens in these patients. The high-risk population of HIV/HCV-coinfected patients is ideal for investigating these questions for two reasons. First, because HIV/HCV-coinfected patients are a priority group for HCV treatment, they will have received treatment over a range of liver disease stages, offering a unique opportunity to investigate the clinical and economic impacts of HCV treatment decisions. Second, ongoing risk of HCV-related outcomes after HCV cure may be more readily detectable in HIV/HCV- coinfected patients, for whom increased immune activation and inflammation may cause lasting damage. The proposed research will consist of cohort studies among members of Kaiser Permanente Northern California. The strengths of this setting include a diverse and generalizable population of 3.8 million members, internal HCV- and HIV-monoinfected comparison groups, an electronic health record (EHR) for identification of key risk factors, and infectious disease registries for high-quality ascertainment of HCV and HIV cases. The specific aims are to 1) determine the effect of early versus deferred HCV treatment on hepatic and extrahepatic outcomes among HCV-monoinfected and HIV/HCV-coinfected patients; 2) evaluate the risk of hepatic and extrahepatic outcomes among HCV-monoinfected and HIV/HCV-coinfected patients after HCV cure, and in a matched group of HIV patients without HCV infection; and 3) determine the cost-effectiveness of HCV treatment for all HCV-monoinfected and HIV/HCV-coinfected patients compared with deferral of treatment to later stages of liver disease. This career development award will provide training in 1) HCV and HIV/HCV epidemiology, treatment, and outcomes; 2) leveraging the EHR for infectious disease research; 3) advanced causal inference methods; and 4) cost-effectiveness analysis. This mentored research and training will directly inform the clinical care of HCV patients and establish my career as an independent researcher in the field.